Gossypol, a complicated dimer of sesquiterpene with multiple biological activities, was isolated from certain species of the cotton plant. The chemical structure was first identified by Adams in 1938 [Adams, R., R. C. Morris, T. A. Geissman, D. J. Butterbaugh, and E. C. Kirkpatrick, J. Am. Chem. Soc., 60:2193 (1938)]and was confirmed by Edwards in 1958 by total synthesis Edwards, J. D., J. Am. Chem. Soc., 80:3798 (1958)].
In recent years, there has been an increased interest in gossypol, due mainly to reports from China that this natural product was identified as the principal agent of the cottonseed oil which causes infertility [National Coordinating Group on Male Antifertility Agents, Chin. Med. J., 4:417 (1978)]. Gossypol has since been reported to exhibit spermicidal effects in vitro [Poso, H., K. Wichmann, J. Janne, and T. Luukkainen, Lancet, 885 (1980)]by inhibition of lactate dehydrogenase X and hence, ATP production [Wichmann, K., K. Kapyaho, R. Sinervirta, and J. Janne, J. Reprod. Fert., 69: 259 (1983)].
Gossypol has been reported to inactivate the enveloped viruses such as parainfluenza type 3 and Herpes simplex viruses [Dorsett, P. H., and E. E. Kerstine, J. Pharm. Sci., 64: 1073 (1975)]. Montamat et al., reported that this natural product was effective in reducing the growth of Trypansoma cruzi, the causative agent of Chaga's disease for which there is no satisfactory drug [Montamat, E. E., C. Burgos, N. M. G. de Burgos, L. E. Rovari, A. Blanco, and E. L. Segura, Science, 218: 288 (1982)]. Human malarial parasite Plasmodium falciparum is also inhibited by this agent [Heiniich, J. E., L. A. Hunsaker, and D. L. Vanda Jagt, IRCS Med. Sci., 11: 304 (1983)].
The study of anticancer activity of gossypol was first reported in 1975, using the leukemia P-388 system [Joland, S. D., R. M. Wiedhaph, and J. R. Cole, J. Pharm. Sci., 64: 1889 (1975)]. More recently, this compound has shown differential cytotoxic effects in human melanoma, colon carcinoma, mammary adenocarcinoma [Rao, P. N., Y-C. Wang, E. Lotzova, A. A. Khan, S. P. Rao and L. C. Stephens, Cancer Chemother. Pharmacol., 15: 20 (1985)] and other tissue culture cell lines [Tuszynsk, G. P., and G. Cussu, Cancer Res., 44: 768 (1984)]. Gossypol is also found to be a potent hyperthermic sensitizer of HeLa cells [Kim, S. H., J. H. Kim, A. A. Alfieri, S. Q. He, and C. W. Young, Cancer Res., 45: 6338 (1985)].
Certain of the compounds disclosed and claimed in the subject application were initially disclosed by the inventors in their article entitled "Anti-Fertility and Other Actions of Gossypol Analogues" and co-authored by M. Sonenberg, J-T. Huang, Y-F. Ren, T-L. Su, K. A. Watanabe, H. C. Haspel, R. E. Corin, and A. P. Hoffer, Contraception, March 1988, Volume 37, Number 3. This article was first mailed to subscribers of Contraception on Apr. 4, 1988.
During the course of studies on the structure-activity relationships of gossypol analogs, the inventors of the subject invention discovered a novel reaction which made it possible to synthesize chemicals having structures quite unrelated to gossypol, yet demonstrating gossypol-like biological activities. This process and the structures produced thereby constitute the present invention.